Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients

Jae Hyun Kim; Nayoung Han; Myeong Gyu Kim; Young Won Kim; Hayoung Jang; Hwi Yeol Yun; Mi Yeon Yu; In Wha Kim; Yon Su Kim; Jung Mi Oh

doi:10.1038/s41598-019-47876-0

Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients

Jae Hyun Kim, Nayoung Han, Myeong Gyu Kim, Young Won Kim, Hayoung Jang, Hwi Yeol Yun, Mi Yeon Yu, In Wha Kim, Yon Su Kim, Jung Mi Oh

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.

Original language	English
Article number	11740
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-47876-0
State	Published - 1 Dec 2019

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© 2019, The Author(s).

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Kim, J. H., Han, N., Kim, M. G., Kim, Y. W., Jang, H., Yun, H. Y., Yu, M. Y., Kim, I. W., Kim, Y. S., & Oh, J. M. (2019). Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients. Scientific Reports, 9(1), Article 11740. https://doi.org/10.1038/s41598-019-47876-0

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title = "Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients",

abstract = "This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.",

author = "Kim, {Jae Hyun} and Nayoung Han and Kim, {Myeong Gyu} and Kim, {Young Won} and Hayoung Jang and Yun, {Hwi Yeol} and Yu, {Mi Yeon} and Kim, {In Wha} and Kim, {Yon Su} and Oh, {Jung Mi}",

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AU - Kim, Young Won

AU - Jang, Hayoung

AU - Yun, Hwi Yeol

AU - Yu, Mi Yeon

AU - Kim, In Wha

AU - Kim, Yon Su

AU - Oh, Jung Mi

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N2 - This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.

AB - This study quantifies the interaction between tacrolimus (TAC) and mycophenolate mofetil (MMF) in kidney transplant recipients. Concentrations of TAC, mycophenolic acid (MPA), and metabolites were analyzed and relevant genotypes were determined from 32 patients. A population model was developed to estimate the effect of interaction. Concentrations of TAC were simulated in clinical scenarios and dose-adjusted trough concentrations per dose (C/D) were compared. Effect of interaction was described as the inverse exponential relationship. Major determinants of trough levels of TAC were CYP3A5 genotype and interaction with MPA. The absolute difference in C/D of TAC according to co-administered MMF was higher in CYP3A5 non-expressers (0.55 ng/mL) than in CYP3A5 expressers (0.35 ng/mL). The effect of MMF in determining the TAC exposure is more pronounced in CYP3A5 non-expressers. Based on population pharmacokinetic model, we suggest the TAC dosing algorithm considering the effects of CYP3A5 and MMF drug interaction in stable kidney transplant recipients.

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Model based development of tacrolimus dosing algorithm considering CYP3A5 genotypes and mycophenolate mofetil drug interaction in stable kidney transplant recipients

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